Viral meningitis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2],Ahmed Elsaiey, MBBCH [3]

Overview

Viral meningitis pathophysiology differs from virus to another and depends on many factors like age, immune status and gene expression. Invasion into the meninges by a pathogen can set up a local inflammatory response. The clinical signs are due to this meningeal irritation - for example, Kernig's sign is due to pain produced by stretching of the inflamed meninges.

Pathogenesis

• The causative viral agents can reach the nervous system via the blood or the nerves themselves. There is a difference in both pathways pathogenesis. Viral spreading through the blood (viremia) is more common in viral meningitis pathogenesis. The viruses enter to the pulmonary and intestinal mucosa at which they spread into the blood to reach the lymph nodes where viral replication takes place and this is called primary viremia. At this point, the host cells try to prevent further replication from happening and if they fail to stop the replication, secondary viremia will take place and the viruses can spread to the nervous system causing many clinical manifestations.

• Enteroviruses:
  • They include coxsackievirus A&B, echovirus, enterovirus, hepatitis A and poliovirus
  • Infection can be started in the nasal mucosa and after that it can be ingested in the stomach. It attaches to the enterocytes then the viruses reach the peyer's patches of the lamina propria where the replication takes place
  • The replication which occurs at this site causes viremia to further organs like the lung, brain and liver at which another replication takes place at these organs causing more viremia. Infetion of the nervous system can occur via this viremia which is responsible for the clinical manifestaions of the disease

• Arboviruses:
  • Common arvboviruses in the United States:
    • St. louis encephalitis virus (Flavivirus)
    • Western equine encephalitis virus (Alphavirus)
    • Colorado tick fever virus (Colitvirus)
  • They commonly cause encephalitis. However, they are responsible for causing viral meningitis.
  • Pathogenesis is similar to the enteroviruses pathogenesis. The difference between them is in the start process of the infection. The infection starts by the arthropod bite to the skin then virus replication takes place in the lymph nodes then viremia occurs in the distant organs and finally the virus reaches the brain.

• Mumps:
  • Infection occurs through respiratory droplet that infects first the parotid gland causing parotitis.
  • After the infection, viremia takes place and the virus reaches the brain causing meningitis.

• Human herpes viruses:
  • They are classified into 3 groups alpha α, beta β, and gamma γ.
  • Alpha group includes:
    • Herpes simplex virus 1
    • Herpes simplex virus 2
  • Beta group includes:
    • Human herpes virus 1
    • Human herpes virus 2
    • Cytomegalovirus
  • Gamma group includes:
    • Human herpes virus 8
    • Epstein barr virus
  • Primary infection by the herpes viruses is like the other viral infections by invasion through the respiratory and gastric mucosa and the replication followed by the viremia till reaching the brain causing meningitis.
  • Latent infection may occur when the virus is stimulated again by tissue damage or exposure to ultraviolet light.

Transmission

Infectious transmission is different among the viruses causing viral meningitis:

• Enteroviruses: Feco-oral transmission and may be transmitted by the respiratory droplet
• Herpes simplex viruse: Interhuman transmission
• Arboviruses: Transmitted through mosquitoes
• Mumps: Transmitted via the blood
• Influenza: Postinfections - airborne transmission
• Lymphocytic choriomeningitis virus: Transmitted by the rodents
• West nile virus: Transmitted via parasitic pathogens

Genetics

There is no genetic inheritance correlated with the viral meningitis.

Pathophysiology

Pathogenesis

Invasion into or past the meninges by a pathogen can set up a local inflammatory response. The clinical signs are due to this meningeal irritation - for example, Kernig's sign is due to pain produced by stretching of the inflamed meninges.

Viruses Associated with the Pathogenesis of Aseptic Meningitis

Many different viruses can cause meningitis. About 90% of cases of viral meningitis are caused by members of a group of viruses known as enteroviruses, such as coxsackieviruses and echoviruses. These viruses are more common during summer and fall months. Herpesviruses and the mumps virus can also cause viral meningitis.

The study of AM is complicated in that there can be a yearly variation in the viruses that are prevalent, as well as differences in geography, diagnostic techniques and the definition of AM.

• One study (from 1960, in the U.S, Europe and the Far East) reported that out of 430 cases of AM, a specific cause was found in 71%.

  • 42% had enterovirus, 22% mumps, 12% poliovirus, 12% lymphocytic choriomeningitis virus, 5% leptospirosis, 2% herpes simplex, 1% arboviruses and <1% had Tuberculosis (TB).
  • If a study like this were to be repeated today, there would obviously be an increase in HIV and Lyme disease (as well as other previously unrecognized causes of AM such as epidural steroid injection and drugs) and a fall in polio and mumps.

• Enteroviruses currently are thought to account for > 80% of identifiable cases of AM.

  • This group (members of the picornavirus family) includes coxsackievirus A&B, echovirus, enterovirus, hepatitis A and poliovirus.
  • Transmission is fecal – oral, and the viruses have a worldwide distribution.
  • Although disease can occur year-round, it peaks in the summer and early fall.
  • Children tend to be affected more commonly than adults, though community and hospital outbreaks can also occur.
  • In addition to the typical presentation of meningitis, patients also tend to have viral exanthems, and may get myopericarditis, conjunctivitis and other typical enteroviral syndromes (i.e. hand-foot and mouth disease).
  • The CSF is typically not helpful and diagnosis typically depends upon identification of the viral antigen by ELISA (enzyme-linked immunosorbent assay).
  • Rx is supportive and the majority of patients do well.
  • In countries that don’t have the polio vaccine, 90% of cases are clinically insignificant, 4-8% will get AM (non-paralytic polio) and < 1% will develop paralytic poliomyelitis.

• Mumps: a paramyxovirus that is spread via respiratory droplets, direct contact and by fomites.

  • Although the incidence in the U.S. had dropped by 95% since the development of the vaccine, it continues to be a major problem worldwide with ~ 1 – 10% of infected patients developing AM.
  • Again, although it can be seen year round, it most commonly occurs in the late winter and spring.
  • Mumps should be specifically suspected when AM follows parotitis, orchitis, oophoritis and pancreatitis.
  • Diagnosis is by culture and the prognosis tends to be excellent.

• Lymphocytic choriomeningitis virus (LCM) is an arenavirus that is spread to humans via contact with rodents or their excrement.

  • LCM AM peaks in the late-fall and early winter, and diagnosis is made via chest x-ray or by seeing a fourfold rise in antibody titer between acute and convalescent sera.

• Herpes simplex virus (HSV) is the most common cause fatal encephalitis in the U.S. and it is crucial to differentiate meningitis from encephalitis.

  • As opposed to encephalitis, which is usually due to HSV-1, meningitis is more frequently caused by HSV-2.
  • The diagnosis is usually clinical (occasionally seen in patients with genital lesions) but the virus can be Cx from the CSF or buffy coat.
  • The prognosis is generally quite good, and it is not clear whether prescription alters the course for mild cases.

• Human immunodeficiency virus (HIV) is an increasingly recognized cause of AM.

  • AM can occur during initial infection as well as during seroconversion.
  • Additionally, HIV can cause recurrent and chronic meningitis, occasionally with cranial nerve abnormalities (esp. V, VII, and VIII).
  • Diagnosis can be made via CSF Cx and polymerase chain reaction (PCR) for viral DNA, though availability is limited.

• Arboviruses typically cause encephalitis, but in their milder forms can cause AM.

  • The most likely of these to present as AM is St. Louis encephalitis, and all typically occur during the warmer months.
  • Diagnosis is made serologically, and is mainly important as a public health measure.
  • Prescription is supportive.

• Other, non-viral infectious causes include:

  • TB: had CN abnormalities in 20 – 30% and is often accompanied by SIADH (inappropriate secretion of antidiuretic hormone), altered MS (multiple sclerosis) and a reduced CSF glucose.
  • Mycoplasma pneumoniae.
  • Listeria monocytogenes: often thought to be aseptic due to a negative gram stain and a slightly higher frequency of a CSF lymphocytosis.
  • Brucellosis: causes neuro disease in < 5% of cases but AM is the most common
  • Leptospirosis, Borrelia, and fungal meningitis (especially crypto, but also cocci and histo) can also be seen.

• The list of non-infectious causes of AM is huge:

  • The most common drugs to cause AM are TMP, TMP-SMX, ibuprofen and other NSAIDs (nonsteroidal anti-inflammatory drugs).

    • Medication induced AM usually has a poly predominant CSF.
    • The mechanism is thought to be an acute hypersensitivity reaction limited to the meninges.

• Sarcoidosis, SLE (systemic lupus erythematosus) and Behçet's disease are the most common systemic illnesses to be associated with AM.

Transmission

Enteroviruses, the most common cause of viral meningitis, are most often spread from person to person through fecal contamination (which can occur when changing a diaper or using the toilet and not properly washing hands afterwards). Enteroviruses can also be spread through respiratory secretions (saliva, sputum, or nasal mucus) of an infected person. Other viruses, such as mumps and varicella-zoster virus, may also be spread through direct or indirect contact with saliva, sputum, or mucus of an infected person. Contact with an infected person may increase your chance of becoming infected with the virus that made them sick; however you will have a small chance of developing meningitis as a complication of the illness.